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1 |
Host transcriptomic signature as alternative test-of-cure in visceral leishmaniasis patients co-infected with HIV
امضای transcriptomic میزبان به عنوان گزینه درمانی جایگزین در بیماران لیشمانیوز احشایی آلوده به HIV-2020 Visceral leishmaniasis (VL) treatment in HIV patients very often fails and is followed by high
relapse and case-fatality rates. Hence, treatment efficacy assessment is imperative but based on invasive
organ aspiration for parasite detection. In the search of a less-invasive alternative and because the host
immune response is pivotal for treatment outcome in immunocompromised VL patients, we studied changes
in the whole blood transcriptional profile of VL-HIV patients during treatment.
Methods: Embedded in a clinical trial in Northwest Ethiopia, RNA-Seq was performed on whole blood samples
of 28 VL-HIV patients before and after completion of a 29-day treatment regimen of AmBisome or AmBisome/
miltefosine. Pathway analyses were combined with a machine learning approach to establish a
clinically-useful 4-gene set.
Findings: Distinct signatures of differentially expressed genes between D0 and D29 were identified for
patients who failed treatment and were successfully treated. Pathway analyses in the latter highlighted a
downregulation of genes associated with host cellular activity and immunity, and upregulation of antimicrobial
peptide activity in phagolysosomes. No signs of disease remission nor pathway enrichment were
observed in treatment failure patients. Next, we identified a 4-gene pre-post signature (PRSS33, IL10, SLFN14,
HRH4) that could accurately discriminate treatment outcome at end of treatment (D29), displaying an average
area-under-the-ROC-curve of 0.95 (CI: 0.751.00).
Interpretation: A simple blood-based signature thus holds significant promise to facilitate treatment efficacy
monitoring and provide an alternative test-of-cure to guide patient management in VL-HIV patients.
Funding: Project funding was provided by the AfricoLeish project, supported by the European Union Seventh
Framework Programme (EU FP7). Keywords: Visceral leishmaniasis | HIV | RNA signature | Treatment efficacy | Blood signature |
مقاله انگلیسی |
2 |
Infection during childhood and the risk of violent criminal behavior in adulthood
عفونت درطی دوران کودکی و خطر رفتارهای جنایتکارانه در بزرگسالی-2020 Infections during brain development appear to contribute to cognitive impairment and aggressive behavior, as
well as to a number of developmental mental disorders closely associated with violent criminal behavior. Yet, no
study has thus far ever investigated whether infections during brain development increases the risk of violent
criminality later in life.
In this population-based cohort study, about 2.2 million individuals born in Sweden between the years 1973
and 1995 were included in an effort to estimate the association between infections during childhood (registered
ICD-10 diagnoses of infections incurred before the age of 14 years) and violent criminal behavior (registered
convictions for a violent crime between the ages of 15 and 38 years, prior to December 31, 2011). After inclusion
of several sociodemographic parameters, risks of violent criminal behavior conferred by childhood infections –
expressed as hazard ratios (HRs) and 95% confidence intervals (CIs) – were calculated by means of Cox regression.
Mediation analyses were performed to explore the effect of psychiatric disorders on the association
between infections during childhood and violent criminality. Results revealed a modest, yet significant, association
between an infection during childhood and violent criminality later in life (adjusted HR 1.14, 95% CI
1.12–1.16). Infections during the first year of life and infections in the central nervous system were associated
with the highest risks of subsequent violent criminality (adjusted HR 1.20, 95% CI 1.18–1.23, and adjusted HR
1.17, 95% CI 1.08–1.26, respectively). The association was partly mediated by the presence of a psychiatric
disorder.
In summary, independent of a wide range of covariates, our results suggest that infections during brain
development could be part of the genesis of violent criminal behavior. Keywords: Criminality | Violence | Psychiatric disorder | Cytokines | Immune response |
مقاله انگلیسی |
3 |
Learning to detect lymphocytes in immunohistochemistry with deep learning
یادگیری لنفوسیت ها در ایمونوهیستوشیمی با یادگیری عمیق-2019 The immune system is of critical importance in the development of cancer. The evasion of destruction by the immune system is one of the emerging hallmarks of cancer. We have built a dataset of 171,166 manually annotated CD3 + and CD8 + cells, which we used to train deep learning algorithms for auto- matic detection of lymphocytes in histopathology images to better quantify immune response. Moreover, we investigate the effectiveness of four deep learning based methods when different subcompartments of the whole-slide image are considered: normal tissue areas, areas with immune cell clusters, and areas containing artifacts. We have compared the proposed methods in breast, colon and prostate cancer tissue slides collected from nine different medical centers. Finally, we report the results of an observer study on lymphocyte quantification, which involved four pathologists from different medical centers, and com- pare their performance with the automatic detection. The results give insights on the applicability of the proposed methods for clinical use. U-Net obtained the highest performance with an F1-score of 0.78 and the highest agreement with manual evaluation ( κ= 0 . 72 ), whereas the average pathologists agreement with reference standard was κ= 0 . 64 . The test set and the automatic evaluation procedure are publicly available at lyon19.grand-challenge.org . Keywords: Deep learning | Immune cell detection | Computational pathology | Immunohistochemistry |
مقاله انگلیسی |
4 |
Innate immunity as the trigger of systemic autoimmune diseases
ایمنی ذاتی به عنوان محرک بیماریهای خود ایمنی سیستماتیک-2019 The innate immune system consists of a variety of elements controlling and participating in virtually all aspects
of inflammation and immunity. It is crucial for host defense, but on the other hand its improper activation is also
thought to be responsible for the generation of autoimmunity and therefore diseases such as autoimmune arthritides
like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) or inflammatory
bowel disease. The innate immune system stands both at the beginning as well as the end of autoimmunity.
On one hand, it regulates the activation of the adaptive immune system and the breach of selftolerance,
as antigen presenting cells (APCs), especially dendritic cells, are essential for the activation of naïve
antigen specific T cells, a crucial step in the development of autoimmunity. Various factors controlling the
function of dendritic cells have been identified that directly regulate lymphocyte homeostasis and in some
instances the generation of organ specific autoimmunity. Moreover, microbial cues have been identified that are
prerequisites for the generation of several specific autoimmune diseases. On the other hand, the innate immune
system is also responsible for mediating the resulting organ damage underlying the clinical symptoms of a given
autoimmune disease via production of proinflammatory cytokines that amplify local inflammation and further
activate other immune or parenchymal cells in the vicinity, the generation of matrix degrading and proteolytic
enzymes or reactive oxygen species directly causing tissue damage. In the last decades, molecular characterization
of cell types and their subsets as well as both positive and negative regulators of immunity has led to the
generation of various scenarios of how autoimmunity develops, which eventually might lead to the development
of targeted interventions for autoimmune diseases. In this review, we try to summarize the elements that are
contributing to the initiation and perpetuation of autoimmune responses. Keywords: Innate immunity | Autoimmunity | Dendritic cells | Pattern recognition receptors | Microbiome in autoimmunity |
مقاله انگلیسی |
5 |
The three-dimensional structure and recognition mechanism of Manduca sexta peptidoglycan recognition protein-1
ساختار و مکانیسم شناختی سه بعدی از شناسایی پروتئین 1 پپتیدوگلیکان ماندوکا sexta-2019 Peptidoglycan recognition proteins (PGRPs) recognize bacteria through their unique cell wall constituent,
peptidoglycans (PGs). PGRPs are conserved from insects to mammals and all function in antibacterial defense. In
the tobacco hornworm Manduca sexta, PGRP1 and microbe binding protein (MBP) interact with PGs and hemolymph
protease-14 precursor (proHP14) to yield active HP14. HP14 triggers a serine protease network that
produces active phenoloxidase (PO), Spätzle, and other cytokines to stimulate immune responses. PGRP1 binds
preferentially to diaminopimelic acid (DAP)-PGs of Gram-negative bacteria and Gram-positive Bacillus and
Clostridium species than Lys-PGs of other Gram-positive bacteria. In this study, we synthesized DAP- and Lysmuramyl
pentapeptide (MPP) and monitored their associations with M. sexta PGRP1 by surface plasmon resonance.
The Kd values (0.57 μM for DAP-MPP and 45.6 μM for Lys-MPP) agree with the differential recognition
of DAP- and Lys-PGs. To reveal its structural basis, we produced the PGRP1 in insect cells and determined its
structure at a resolution of 2.1 Å. The protein adopts a fold similar to those from other PGRPs with a classical Lshaped
PG-binding groove. A unique loop lining the shallow groove suggests a different ligand-binding mechanism.
In summary, this study provided new insights into the PG recognition by PGRPs, a critical first step that
initiates the serine protease cascade Keywords: Insect immunity | Pattern recognition | Hemolymph protein | Serine protease | Prophenoloxidase activation | Melanization |
مقاله انگلیسی |
6 |
A novel C1q domain containing protein in black rockfish (Sebastes schlegelii) serves as a pattern recognition receptor with immunoregulatory properties and possesses binding activity to heat-aggregated IgG
دامنه C1q رمان حاوی پروتئین در ماهی سیاه (Sebastes schlegelii) به عنوان یک گیرنده به رسمیت شناختن الگو با خواص سیستم ایمنی بدن عمل می کند و دارای فعالیت اتصال به IgG با حرارت است:-2019 C1q-domain-containing (C1qDC) proteins, which are involved in a series of immune responses, are important pattern recognition receptors in innate immunity in vertebrates and invertebrates. Functional studies of C1qDC proteins in vertebrates are scarce. In the present study, a C1qDC protein (SsC1qDC) from the teleost black rockfish (Sebastes schlegelii) was identified and examined at expression and functional levels. The open reading frame of SsC1qDC is 636 bp, and the predicted amino acid sequence of SsC1qDC shares 62%–69% overall identity with the C1qDC proteins of several fish species. SsC1qDC possesses conserved C1qDC features, including a signal sequence and a C1q domain. SsC1qDC was expressed in different tissues and its expression was up- regulated by bacterial and viral infection. Recombinant SsC1qDC (rSsC1qDC) exhibited apparent binding ac- tivities against PAMPs including LPS and PGN. rSsC1qDC had antibacterial activity against Vibrio para- haemolyticus, and was able to enhance the phagocytic activity of macrophages towards Vibrio anguillarum. rSsC1qDC interacted with human heat-aggregated IgG. Furthermore, in the presence of rSsC1qDC, fish exhibited enhanced resistance against bacterial infection. Collectively, these results indicated that SsC1qDC serves as a pattern recognition receptor and plays a vital role in the defense system of black rockfish. Keywords: C1q-domain-containing protein | Sebastes schlegelii | Immune defense | Pattern recognition receptor | Antibacterial activity |
مقاله انگلیسی |
7 |
Scavenger receptor class B type I (SR-BI) in Ruditapes philippinarum: A versatile receptor with multiple functions
گیرنده کلاس B نوع I (SR-BI) در Ruditapes philippinarum: یک گیرنده همه کاره با عملکردهای مختلف-2019 In the present study, a scavenger receptor class B type I (designed as RpSR-BI) was cloned and characterized from
manila clam Ruditapes philippinarum. The full-length cDNA of RpSR-BI was of 2000 bp, containing an open
reading frame (ORF) of 1515 bp. Multiple alignments and phylogenetic analysis strongly suggested that RpSR-BI
was a member of the scavenger receptors family. The mRNA transcript of RpSR-BI was constitutively expressed
in all tested tissues, and mainly expressed in hepatopancreas and hemocytes. Generally, Vibrio anguillarum or
Micrococcus luteus challenge induced the expression of RpSR-BI transcripts in hemocytes of manila clams.
Recombinant protein of RpSR-BI (rRpSR-BI) could bind lipopolysaccharides, peptidoglycan and glucan, but not
chitin in vitro. Coinciding with the PAMPs binding assay, a broad agglutination spectrum was displayed by
rRpSR-BI including Gram-positive bacteria and Gram-negative bacteria. Moreover, rRpSR-BI could enhance the
phagocytosis and chemotaxis of hemocytes. These results showed that RpSR-BI functioned as a pattern recognition
receptor (PRR) with distinct recognition spectrum, and also as an opsonin involved in the innate
immune response of R. philippinarum. Keywords: Ruditapes philippinarum | Scavenger receptor | Pattern recognition receptor | Immune recognition |
مقاله انگلیسی |
8 |
Characterization and functional analysis of a novel mannose-binding lectin from the swimming crab Portunus trituberculatus
خواص و تجزیه و تحلیل عملکرد از یک لکتین مانوز، رویکردی از خرچنگ شناگر Portunus trituberculatus-2019 Mannose-binding lectin (MBL) is a pattern recognition receptor (PRR) that plays an important role in the innate
immune response. In this study, a novel mannose-binding lectin was cloned from the swimmimg crab Portunus
trituberculatus (designated as PtMBL). The complete cDNA of PtMBL gene was 1208 bp in length with an open
reading frame (ORF) of 732 bp that encoded 244 amino acid proteins. PtMBL shared lower amino acid similarity
with other MBLs, yet it contained the conserved carbohydrate-recognition domain (CRD) with QPD motif and
was clearly member of the collectin family. PtMBL transcripts were mainly detected in eyestalk and gill with
sexually dimorphic expression. The temporal expression of PtMBL in hemocytes showed different activation
times after challenged with Vibrio alginolyticus, Micrococcus luteus and Pichia pastoris. The recombinant PtMBL
protein revealed antimicrobial activity against the tested Gram-negative and Gram-positive bacteria. It could
also bind and agglutinate (Ca2+-dependent) both bacteria and yeast. Furthermore, the agglutinating activity
could be inhibited by both D-galactose and D-mannose, suggesting the broader pathogen-associated molecular
patterns (PAMPs) recognition spectrum of PtMBL. These results together indicate that PtMBL could serve as not
only a PRR in immune recognition but also a potential antibacterial protein in the innate immune response of
crab Keywords: Portunus trituberculatus | Mannose-binding lectin | Pattern recognition receptor | Antimicrobial activities |
مقاله انگلیسی |
9 |
A toll receptor is involved in antibacterial defense in the oriental river prawn, Macrobrachium nipponense
گیرنده عوارض در دفاع ضد باکتریایی در میگو رودخانه شرقی ، Macrobrachium nipponense نقش دارد-2019 Toll-like receptors (TLRs) play an important role in the activation of innate immune response in animals. In this
study, we identified a TLR from the oriental river prawn, Macrobrachium nipponense (MnToll1) and investigated
its functions in immunity. The MnToll1 protein shares similar structural characteristics with other known Toll
family proteins. MnToll1 transcripts are broadly distributed in all of the examined tissues, and its expression level
was significantly up-regulated by bacterial challenge. RNAi-mediated knockdown of MnToll1 significantly impaired
the survivability of Vibrio-challenged prawns. RNAi experiments also revealed that the expression of
several antimicrobial peptide genes were regulated by MnToll1. Moreover, we found the extracellular region of
MnToll1 could directly bind to bacteria and bacterial glycoconjugates. These findings suggest that MnToll1
function as a pattern recognition receptor to recognize invading pathogen and initiate downstream gene expression,
to participate in antibacterial defense of M. nipponense. Keywords: Macrobrachium nipponense | Toll receptor | Pattern recognition receptor | Antimicrobial peptide | Innate immunity |
مقاله انگلیسی |
10 |
Immune recognition, antimicrobial and opsonic activities mediated by a sialic acid binding lectin from Ruditapes philippinarum
تشخیص ایمنی ، فعالیت ضد میکروبی و اپسونیک به واسطه یک لکتین اتصال اسید سیالیک از Ruditapes philippinarum-2019 In the present study, a sialic acid-binding lectin was identified and characterized from Manila clam Ruditapes
philippinarum (designed as RpSABL-1). Multiple alignments strongly suggested that RpSABL-1 was a new member
of the sialic acid-binding lectin family. In non-stimulated clams, RpSABL-1 transcripts were constitutively expressed
in all five tested tissues, especially in hepatopancreas. After Vibrio anguillarum challenge, the expression
of RpSABL-1 mRNA was significantly up-regulated at 6 h (P < 0.05), 12 h (P < 0.01) and 24 h (P < 0.01).
Recombinant RpSABL-1 protein (rRpSABL-1) displayed apparent binding activities towards lipopolysaccharides
(LPS) and peptidoglycan (PGN), but not to glucan or chitin in vitro. Coinciding with the PAMPs binding assay,
rRpSABL-1 exhibited obvious agglutination activities against Gram-positive bacterium Staphyloccocus aureus,
Gram-negative bacteria Escherichia coli, V. anguillarum and Vibrio harveyi. Meanwhile, rRpSABL-1 showed antibacterial
activities against E. coli, and biofilm formation of E. coli could also be inhibited after incubated with
rRpSABL-1. Moreover, the encapsulation, phagocytosis and chemotactic ability of hemocytes could be enhanced
by rRpSABL-1. All these results suggested that RpSABL-1 could function as a pattern recognition receptor with
versatile functions in the innate immune responses of R. philippinarum. Keywords: Ruditapes philippinarum | Sialic acid-binding lectin | Pattern recognition receptor | Immune recognition |
مقاله انگلیسی |